Ethanol is metabolized by 2 enzymes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). cDNA probes and genomic DNA probes have been utilized to investigate genetic variation at the ADH and ALDH loci, the mapping relationships of ADH genes, factors involved in regulation of ADH gene expression in different tissues and during development, and the altered expression of ADH in liver tumors. Results of these studies have led to the identification of population differences in the frequencies of ADH DNA polymorphisms. Studies have also been carried out to define whether specific ADH DNA polymorphisms are in linkage disequilibrium with ADH kinetic variations. The map relationships of ADH and 12 other markers on human chromosome 4 have been established. A study of ADH mRNA in adult liver, fetal liver, intestine and lung, and analysis of sequence data revealed that for a particular ADH gene the polyadenylation site which is predominantly used varies in different tissues and may vary in development. Analysis of ADH3 in hepatomas revealed allele loss in three out of five hepatomas. DNA alterations at the epidermal growth factor locus (known to be linked to ADH3) were also observed in three tumors, suggesting that structural changes in the 4q21-4q27 region occur in a significant proportion of hepatomas. A search for polymorphisms of human mitochondrial A1DH has been initiated.